Myoblast fusion is essential for skeletal muscle development and repair following injury or degeneration. Although a number of factors have been implicated in myoblast fusion, the precise mechanism of this process remains unknown. A better understanding of the molecular events associated with fusion is, therefore, required before one can plan strategies aimed to enhance muscle repair or to optimize gene therapies employing myoblasts as vehicles for targeted gene delivery into diseased muscle. In the proposed studies, we will investigate a role of ADAM 12, a member of the ADAM family of proteins (containing A Disintegrin And Metalloprotease domain) in myoblast fusion. We hypothesize that the disintegrin domain of ADAM 12 binds to an integrin receptor in myoblast membrane and that ADAM-integrin interactions provide a mechanism of myoblast self-recognition that leads to fusion. Our long-term goal is to extend these studies to other domains of ADAM 12 and to obtain a comprehensive understanding of ADAM 12 function in myoblast communication and fusion. First, we will investigate if the region of ADAM 12 that is homologous to soluble disintegrins constitutes an autonomous protein domain and has a potential to execute a distinct biochemical function. Then, we will identify a receptor from myoblast plasma membrane that can interact with the disintegrin domain. Using site-directed mutagenesis, we will determine what residues and what structural signatures of the disintegrin domain are critical for the interactions. If the newly identified receptor belongs to the integrin family, we will investigate if binding of disintegrin triggers any of the known integrin signaling pathways. Finally, we will evaluate the importance of the disintegrin- mediated adhesion in myoblast fusion by studying the effects of blocking or eliminating the interactions between the disintegrin domain of ADAM 12 and its receptor.